الفهرس | Only 14 pages are availabe for public view |
Abstract Summary 85 Neuropsychological studies available reveal a considerably high prevalence of abnormal intelligence quotient (IQ), not correlating, however, to factors such as hypoxia or iron overload. It is proposed that factors associated to severe chronic illness, rather than the disease per se, could be responsible for these findings (Zafeiriou et al., 2006). Our study is a part of a continum of a previously done study in (2013) by Badir on the same group of patients where they studied 60 child diagnosed with β-TM (on basis of transfusion dependent microcytic hypochromic anemia early in life with elevated hemoglobin F level).They were recruited from Hematology Outpatient Clinic Ain Shams University in the period from April 2011 to January 2012. They were divided according to their compliance to iron chelating therapy (receiving ≥ 70 % of previosly planned iron chelating therapy protocol for 6 months prior to the study) . A ccordingly , patients were divided into into 2 groups; Group A: compliant to iron chelating therapy and Group B: Non-compliant to iron chelating therapy. Those with auditory problems, neurological complaints, thyroid hormone dysfunction, or Vitamin B12 deficiency were excluded from the study. They were compared to 40 age and sex matched apparently healthy controls. Summary 86 After obtaining a verbal consent from the included subjects they were subjected to careful history taking and a through physical examination in addition to serum ferritin level in the last three months and evaluating the ferritin trend in the past three years. All studied groups were subjected to Neuropsychological Testing using: Wechsler Intelligence Scale for Children forth edition (WISC IV): (Wechsler, 1991), Benton Visual Retention Test: (Benton, 1963) and Wisconsin Card Sort Test: (Wisconsin, 1987) and their results revealed that different neurophysiological functions studied were significantly impaired in non compliant patients compared to compliant patients as well as the controls with significant impairment in those receiving desferrioxamine (DFO) and significant correlation was observed with serum ferritin, suggesting that BTM is associated with neuropsychological impairment involving multiple cognitive domains and argue for a potential role of hemosiderosis and DFO on cognitive functioning. Hence we aimed at uncovering the relation between neurocognitive impairment, serum fetritin and different iron chelators with cerebral intracellular metabolites by doing MRS to those patients. Summary 87 The major peaks of the proton MRS, corresponding to Nacetylaspartate (NAA), creatine (Cr), have been previously used to evaluate neuronal loss and active neurons breakdown. The ratio of NAA to Cr (NAA/Cr) is considered a metabolic marker reflecting the functional status of neurons and axons in the brain, with a decrease indicating neuronal or axonal loss or dysfunction (Watanabe et al., 2004). NAA / Cr ratio has been useful in predicting the degree of injury and potential recoverability of brain damage following head injury (Moffett et al., 2007). Reduction of cerebral NAA/Cr ratio may be reversible; thus, it can be used as a dynamic marker of neuronal dysfunction and integrity and cognitive functions (Demougeot, 2001). However, the relation between NAA/Cr ratio and neuro cognitive tests in BTM patients needs to be further elucidated. So we were especially interested in studying NAA/Cr ratio in our cases and compare it with previously mentioned variables. NAA is a free amino acid that is synthesized fromacetyl coenzyme A and aspartate by D-aspartate Nacetyltransferase in the mitochondria of neurons (Neale et al., 2000). Summary 88 NAA is believed to be almost exclusively located in neurons and neuronal processes such axons and dendrites. Thus, NAA is expected to be a marker of neuro/axonal integrity at 1H MRS (Miller, 1991).Pathologies that cause neuronal loss or neuro/axonal dysfunction decrease the level of NAA at 1HMRS. Chenga et al. (2002) demonstrated that NAA level in brain is correlated with neuronal density. It has also been shown that increased neuro/axonal activity in pathological and physiological conditions might increase NAA level (Aydin et al., 2005) In white matter, NAA is predominantly present in axons. Therefore, the NAA concentration in white matter is related to the structural and functional integrity of the myelinated axonal fibers (Appenzeller et al., 2005; Bjartmar et al., 2002; chard et al., 2002a, 2002b; Lentz et al., 2005). The correlation of NAA concentration with IQ scores might indicate a variation in axonal density between the subjects that affects intellectual performances. Higher NAA concentration in frontal lobe might reflect a higher number of axonal fibers connecting cerebral hemispheres. (Aydin et al.,2012) Summary 89 NAA level in white matter is correlated and associated with the progression and maturation of myelination process. It is well known that myelin increases axonal conduction velocity, Thus, a variation in the degree of myelination of neuronal fibers between the subjects might lead to the significant differences in the IQ test performances. Higher axonal density and/or greater degree of axonal myelination lead to more efficient inter-hemispheric data transfer that may enhance intellectual performance. (Aydin et al.,2012) In out study , reduced NAA/Cr was observed in only 78.3% of cases with normal NAA/Cr in all control group subjects. Its reduction reflects neuronal loss, lower neuronal density, atrophied dendrites and axons, and/or deranged neuronal metabolism (Ross &Bluml ., 2001). Hasegawa et al. in (2011) investigated the effects of ferritin overexpression in the brain by H-MRS on the mices there was significantly altered some metabolic markers in mice brains, such as decrease in myo-inositol and glutamine, an increase in lactate were observed with no specific changes in NAA, creatine, choline & alanine and this is in accordance to our findings. Summary 90 The relationship between frontal lobe NAA/Cr ratio and neuropsychological tests associated with frontal lobe function was confirmed in a study on healthy children in (2009) by Ozturk et al. Further more, in (2012) Aydin et al. studied metabolite concentrations in the brain and intelligence among 30 adolescents using the Wechsler Intelligence Scale for Children (verbal, performance and full-scale IQ) test, and they found a significant positive correlation between performance IQ and full-scale IQ scores and NAA concentration. In the same domain, Grazioli et al. (2008) studied patients with multiple sclerosis and found that patients with lowest frontal lobe NAA/Cr ratio performed significantly worse on the memory test.. In our study, there was a significant positive correlation between NAA/Cr and Wechsler Intelligence Scale for Children, and patients with reduced NAA /Cr ratio had a significantly higher abnormal scores on Benton Visual Retention Test (BVRT) with a significant negative correlation between NAA/Cr and BVRT. Also, Wisconsin Card Sort Test scores were significantly lower in patients with reduced NAA/Cr ratio and WCST showed a significant positive correlation with NAA/Cr ratio Summary 91 Additionally reduced NAA/Cr ratio is a marker of cortical neuronal loss and dysfunction in schizophrenia. In 2009 Pedersen et al they correlated the level NAA/Cr with performance on the dynamic WCST in patients with schizopherenia as well as healthy subjects. And a significant correlation was observed between NAA/Cr and learning potential on WCST. ALSO Galińska et al.( 2007) found that Cognitive impairment related to dysfunction of the prefrontal cortex in first-episode schizophrenia is associated with reduction of NAA /Cr in the frontal lobe. AND NAA/Cr in the frontal lobe were significantly related to poorer WCST performance. Also, Reduced NAA/Cr ratio is a marker of cortical neuronal loss and dysfunction in amyotrophic lateral sclerosis (ALS). Moreover, NAA levels in the motor area and frontal lobe correlate with the clinical features ALS, including frontal lobe function (Abe et al., 2001). As per their study in 2001, Abe et al. found that the NAA/Cr ratio was reduced in the motor area and frontal lobe of the brain of 14 patients with clinically definite (ALS) compared to controls with a significant correlations between the NAA/Cr ratio and the number of categories achieved in the Wisconsin Card Sorting test, implying frontal lobe dysfunction |